3126 – PERSISTENT METABOLIC DEFLATION OF HEMATOPOIETIC STEM CELLS (HSCS) AFTER CHEMOTHERAPY CAUSES PREMATURE HEMATOPOIETIC AGEING

• Published in: Experimental hematology Vol. 137; p. 104447
• Main Authors: Mansell, Els, van Tienhoven, Tim, Sjoberg, Julia, Lepland, Johanna, Rydstrom, Anna, Bucakci, Akin, Maaskant, Wout, Enver, Tariq, Larsson, Jonas, Raaijmakers, Marc, Sigurdsson, Valgardur
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-08-2024
• ISSN: 0301-472X
• DOI: 10.1016/j.exphem.2024.104447

Hematopoietic recovery between cycles of chemotherapy is critical for treatment continuation and outcome. Hematopoietic recovery is frequently defined based on neutrophil and platelet counts. Although this is clinically meaningful, we are intrigued by the possibility that ’hidden’ incomplete recovery of other lineages and uncommitted progenitors after chemotherapy may have significant consequences.
To this end, we exposed young adult mice to three rounds of chemotherapy (Fluorouracil, Cytarabine or Doxorubicin), at 21-day intervals to allow full quantitative hematopoietic recovery between cycles and prior to endpoint analyses (Sigurdsson, Blood adv., 2020).
Despite rapid and complete recovery of total nucleated cell counts and platelets, we observed striking and persistent differences in hematopoiesis in chemotherapy-exposed mice. These included myeloid bias, anaemia and thrombocytosis, strongly resembling natural ageing.
Having previously shown that HSC ageing coincides with decreased mitochondrial activity (Mansell, Cell Stem Cell, 2021), we herein kinetically modelled the metabolic response of HSCs to chemotherapy. Strikingly, we found a lack of metabolic recovery specific to HSCs in terms of mitochondrial content and mitochondrial membrane potential (ΔΨm). This metabolically deflated state coincides with decreased function upon competitive transplantation, evident by reduced and myeloid-biased engraftment. To test whether the lack of mitochondrial recovery is causative of this HSC dysfunction, we pharmacologically targeted mitochondria using mitoquinol (Mito-Q). Strategic Mito-Q treatments did indeed result in accelerated bone marrow recovery and rescued B-lymphopoiesis upon transplantation.
We conclude that chemotherapy exposure induces premature hematopoietic ageing that is relevant and may be rescued through strategic use of mitochondrial-targeted treatments.